There are >10,000 species of venomous marine snails belonging to the superfamily Conoidea; one group in the superfamily are the cone snails (Conus). The general goal of this program is to develop highly selective peptide ligands derived from Conoidean venoms that have novel pharmacological specificity for various ion channel and receptor subtypes. Our laboratories have previously isolated such peptides from Conus venoms, and these have been used extensively in basic research by many laboratories, and important translational applications have emerged. In particular, Conus peptides have uncovered novel mechanisms to alleviate pain. A general goal of this Program is to develop highly selective peptide ligands for novel targets. In the next grant period, we plan to expand the general biological resource to be accessed, from the venoms of the 700 cone snails to the venomous snails in the entire family of Conoidea. The discovery activities of this Program follow a cladistic strategy that was convincingly validated in the last grant period. We believe that this discovery strategy represents a potential paradigm shift in how discovery of lead compounds from animal biodiversity will be carried out in the future. The cladistic discovery strategy is more systematic, science based and efficient than the usual procedures for bioprospecting. The Program is organized into four Cores and four Projects. Together, the Cores support all of the discovery activities of this Program, including a significant number of discovery initiatives that are not supported by any of the Projects. Furthermore, the Cores will also strengthen the scientific foundation required for extending the cladistic discovery strategy to all groups in the superfamily Conoidea. The goals of the Projects are to develop panels of highly subtype-specific peptide ligands for the nicotinic receptor family, for the sodium channel family, for the G-protein coupled-peptide receptor family, and for K channels. Each project also has specific translational applications, including the development of analgesic compounds for pain and cardioprotective compounds for myocardial infarction due to ischemia. An experimental plan to clarify basic mechanisms that underlie each translational application will be pursued. This discovery program has led to one compound already approved as a commercial drug, and many others that have either reached human clinical trials or are in advanced preclinical development. The cladistic strategy to be employed, and the larger biological resource to be accessed, should greatly accelerate the pace of discovery ultimately leading to novel translational applications. Thus, the research activities of this program interact broadly with the basic research community studying ion channels and receptors, as well as the more clinically oriented community developing novel therapeutic and diagnostic applications.